What is Kisunla (donanemab) and what are its adverse effects and safety considerations?

Kisunla (Donanemab): Overview and Adverse Effects

Kisunla (donanemab-azbt) is an FDA-approved monoclonal antibody for treating early symptomatic Alzheimer's disease that targets amyloid plaques in the brain, but carries significant risks including brain swelling (ARIA-E in 24% of patients), brain microbleeds (ARIA-H in 25%), and infusion reactions requiring mandatory MRI monitoring. 1

What is Kisunla?

Kisunla is a humanized IgG1 monoclonal antibody that specifically targets N-terminal pyroglutamate-modified amyloid beta plaques—a hallmark pathology of Alzheimer's disease. 1, 2 It received traditional FDA approval in June 2024 for adults with mild cognitive impairment or mild dementia due to Alzheimer's disease who have confirmed amyloid pathology. 3, 4

Mechanism of Action

• Donanemab binds to insoluble N-truncated pyroglutamate amyloid beta deposits in brain plaques, facilitating their clearance through immune-mediated mechanisms. 1
• Clinical trials demonstrated 86.4 Centiloid reduction in amyloid plaque burden compared to placebo at 76 weeks, with effects observable starting at week 12. 1
• The drug also reduces plasma p-tau217 levels, suggesting effects on tau pathophysiology beyond amyloid clearance alone. 3

Clinical Efficacy

• In the TRAILBLAZER-ALZ 2 trial, donanemab slowed cognitive decline by 35% on the iADRS scale and 36% on the CDR-SB scale in patients with low-to-medium tau burden. 5, 6
• The treatment difference was 3.25 points on iADRS (scale 0-144) and -0.67 points on CDR-SB (scale 0-18) at 76 weeks in the low/medium tau population. 5
• A unique feature is the ability to discontinue treatment once amyloid clearance is achieved (below 24.1 Centiloids), unlike other anti-amyloid therapies requiring continuous administration. 3

Major Adverse Effects and Safety Concerns

Amyloid-Related Imaging Abnormalities (ARIA)

ARIA represents the most significant safety concern with donanemab, requiring intensive MRI surveillance:

• ARIA-E (edema/effusion): Occurred in 24% of donanemab-treated patients versus 2% on placebo, with 52 symptomatic cases. 1, 5
• ARIA-H microhemorrhages: Affected 25% of patients on donanemab compared to 11% on placebo. 1
• ARIA-H superficial siderosis: Occurred in 15% versus 3% on placebo. 1
• APOE ε4 carriers are approximately 4 times more likely to experience ARIA-E events by 24 weeks regardless of drug exposure levels. 3

Infusion-Related Reactions

• Infusion-related reactions occurred in 9% of donanemab patients versus 0.5% on placebo. 1
• Patients who developed anti-drug antibodies (approximately 10%) had higher rates of infusion reactions compared to those without antibodies (2%). 1

Hypersensitivity and Anaphylaxis

• Hypersensitivity reactions, including anaphylaxis, occurred in 3% of donanemab-treated patients versus 0.7% on placebo. 1

Gastrointestinal Complications

• Intestinal obstruction: 0.4% (3 patients) on donanemab versus 0% on placebo. 1
• Intestinal perforation: 0.2% (2 patients) on donanemab versus 0.1% (1 patient) on placebo. 1

Common Adverse Effects (≥5% and ≥2% higher than placebo)

• Headache: 13% versus 10% on placebo 1
• The ARIA-related events listed above 1

Treatment-Related Deaths

• Three deaths in the donanemab group and one in the placebo group were considered treatment-related in the TRAILBLAZER-ALZ 2 trial. 5

Mandatory Safety Monitoring Requirements

Pre-Treatment Screening

• Baseline brain MRI (within 12 months of treatment initiation) to exclude patients with >4 cerebral microbleeds, cortical superficial siderosis, or major vascular contributions to cognitive impairment. 2
• APOE genotyping must be performed to assess individual ARIA risk before initiating therapy. 2
• Biomarker confirmation of amyloid pathology via PET scan, CSF testing, or validated blood biomarkers (plasma p-tau217). 3, 2

During-Treatment MRI Surveillance

Mandatory MRI monitoring schedule to detect ARIA: 2

• Prior to the 2nd infusion (approximately week 4)
• Prior to the 3rd infusion (approximately week 8)
• Prior to the 4th infusion (approximately week 12)
• Prior to the 7th infusion (approximately week 24)
• Prior to the 12th infusion in higher-risk individuals (APOE ε4 carriers)
• At any time ARIA is clinically suspected

ARIA Management

• ARIA may require temporary or permanent cessation of therapy and corticosteroid treatment depending on severity. 2
• Symptomatic ARIA occurred in 52 patients in clinical trials, necessitating close clinical monitoring. 5

Patient Eligibility Criteria

Who Should Receive Donanemab

• Patients with mild cognitive impairment (CDR 0.5) or mild dementia (CDR 1.0) due to Alzheimer's disease 7, 2
• MMSE score 20-30 or MoCA ≤25 documenting objective cognitive impairment 2
• Confirmed amyloid pathology by PET, CSF, or blood biomarkers 3, 2
• Documented functional impairment on standardized scales (ADCS-iADL) 7

Who Should NOT Receive Donanemab

• Cognitively unimpaired individuals, even with positive amyloid biomarkers (preclinical stage) 3, 7
• Patients with subjective cognitive decline without objective impairment 7
• Individuals with >4 cerebral microbleeds or cortical superficial siderosis on baseline MRI 2
• Patients with suspected Lewy body dementia or other non-AD dementias 3

Administration and Practical Considerations

Dosing Regimen

• Initial dosing: 700 mg IV every 4 weeks for 3 doses 7
• Maintenance dosing: 1400 mg IV every 4 weeks thereafter 7
• Treatment may be discontinued once amyloid clearance is demonstrated on PET scan, typically at 12-18 months. 2

Infrastructure Requirements

• Treatment requires multidisciplinary teams with specialized training in ARIA detection and management. 3, 8
• Enrollment in CMS-approved registry is mandatory for Medicare reimbursement. 3, 7
• Hub-and-spoke care models are being developed to address specialist shortages and expand access. 8

Important Clinical Caveats

• Tau burden stratification is crucial: Patients with high tau burden show reduced clinical benefit compared to those with low-to-medium tau levels. 3
• Shared decision-making is essential: The modest clinical benefits (approximately 30% slowing of decline) must be weighed against significant ARIA risks and monitoring burden. 2
• Long-term data beyond 18 months are limited: Postmarketing surveillance and extended follow-up studies are ongoing. 9
• Cardiovascular risk factors should be rigorously managed, though donanemab has a more favorable cardiovascular profile than some other disease-modifying therapies. 10